Modafinil (C15H15NO2S) of formula I, 2-(benzhydrylsulphinyl)-acetamide, is a synthetic acetamide derivative possessing wakefulness-promoting activity, whose structure has been described in U.S. Pat. No. 4,177,290 and whose racemic form has received the approval of the registration authorities for use in the treatment of narcolepsy.

Example 1 (scheme 1) of U.S. Pat. No. 4,177,290 (Lafon) describes a process for preparing modafinil which comprises reacting benzhydrylthioacetic acid with thionyl chloride in a first step. The acid chloride obtained is then reacted with ammonia to give the corresponding acetamide. Finally, in a last step, the sulphur atom of this intermediate is oxidized in the presence of hydroperoxide in acetic acid to give modafinil.

The drawback of this process is that the step of oxidizing the sulphur of the 2-[(diphenylmethyl)thio]acetamide intermediate in the presence of hydrogen peroxide is difficult to control and may lead to the formation of a sulphone by-product (II) which is difficult to separate from the modafinil.

Patent application WO 02/10125 (TEVA) describes a process for preparing modafinil which takes the same kind of approach. In this application, however, the step of oxidizing the sulphur of the 2-[(diphenylmethyl)thio]acetamide is carried out using hydrogen peroxide in the presence of a mineral acid such as H2SO4, HClO4 or H3PO4 and a linear, branched or cyclic alcohol or a phase transfer catalyst, optionally in an inert organic solvent.
According to the authors these conditions are particularly suitable for the oxidation of sterically hindered sulphides such as modafinil and allow the oxidation step to be controlled and in particular the formation of the sulphone by-product (II) to be avoided.
Example 1a of U.S. Pat. No. 4,177,290 (scheme 2) proposes a quite different approach for the industrial-scale preparation of modafinil. Thus the oxidation of the sulphur atom of benzhydrylthioacetic acid in the presence of hydrogen peroxide takes place in the first step. The intermediate obtained is then converted to the methyl ester, i.e. methyl diphenylmethylsulphinyl-acetate (DMSAM), by reaction with dimethyl sulphate. Finally, after gaseous ammonia has been bubbled into a methanolic solution of DMSAM for one hour, the reaction mixture is left in contact for four hours. The modafinil thus obtained is isolated and recrystallized in two stages.

This preparation process, however, has drawbacks. In particular it involves a plurality of steps of recrystallization of the modafinil obtained, and presents a mediocre yield.
U.S. Pat. No. 4,927,855 (Lafon) describes the synthesis of levorotary modafinil by reaction of a 0.3 mol·L−1 solution of (−)-DMSAM with ammonia at ambient temperature. Following recrystallization, however, the levorotary modafinil is obtained with a modest yield.
Studies have shown, moreover, that the particle size of the modafinil has a great influence on the pharmacological efficacy of the compound.
Thus, according to application WO 96/11001 (Cephalon), small modafinil particles induce an increase in the pharmacological efficacy of modafinil, probably by promoting its absorption as compared with larger particles.
In that context the said application describes pharmaceutical compositions comprising a homogeneous mixture of modafinil particles of defined granulometry (mean (2 to 19 μm), median (2 to 60 μm)). These particles are obtained after grinding of the modafinil prepared by the conventional methods, in order to reduce the size of the particles or aggregates, followed by screening of the resultant particles to give a defined particle size distribution.
Furthermore, racemic modafinil can be obtained in different polymorphic forms or in the form of a mixture of these polymorphs, depending on the operating conditions employed (WO 02/10125 (TEVA)).
Since the various polymorphs of modafinil may present very different physical, pharmaceutical, physiological and biological properties it is important to have available a preparation process which allows one single polymorph to be obtained with simplicity and rapidity.